PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I-binding peptides in vivo

Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
European Journal of Immunology (Impact Factor: 4.03). 04/2011; 41(4):926-35. DOI: 10.1002/eji.201041040
Source: PubMed


Proteasomes play a fundamental role in the processing of intracellular antigens into peptides that bind to MHC class I molecules for the presentation of CD8(+) T cells. Three IFN-γ-inducible catalytic proteasome (immuno)subunits as well as the IFN-γ-inducible proteasome activator PA28 dramatically accelerate the generation of a subset of MHC class I-presented antigenic peptides. To determine whether these IFN-γ-inducible proteasome components play a compounded role in antigen processing, we generated mice lacking both PA28 and immunosubunits β5i/LMP7 and β2i/MECL-1. Analyses of MHC class I cell-surface levels ex vivo demonstrated that PA28 deficiency reduced the production of MHC class I-binding peptides both in cells with and without immunosubunits, in the latter cells further decreasing an already diminished production of MHC ligands in the absence of immunoproteasomes. In contrast, the immunosubunits but not PA28 appeared to be of critical importance for the induction of CD8(+) T-cell responses to multiple dominant Influenza and Listeria-derived epitopes. Taken together, our data demonstrate that PA28 and the proteasome immunosubunits use fundamentally different mechanisms to enhance the supply of MHC class I-binding peptides; however, only the immunosubunit-imposed effects on proteolytic epitope processing appear to have substantial influence on the specificity of pathogen-specific CD8(+) T-cell responses.

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Available from: E.J.A.M. Sijts
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    • "The subunit replacements and the association of the 11S regulator to at least one end of the 20S core alter the cleavage pattern of the proteasome, optimizing the generation of small peptides for loading on the groove of MHC class I molecules [25]–[27]. These changes are also related to increase the production of immunogenic peptides compared to standard proteasome [28], [29]. "
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